Diclofenac sodium (Monosodium 2-(2,6-dichloroanilino) phenyl acetate, C14H10C12NNaO2) is a nonsteroidal drug having analgesic, anti-inflammatory and anti-rheumatic effects which was developed by CIBA-GEIGY AG in Switzerland (now, Novartis Pharma AG) in 1965. This drug has a strong action and a low toxicity compared with indomethacin or the like, and therefore is widely subjected to current clinical use.
The commercially available diclofenac sodium pharmaceuticals include tablets, delayed-release pharmaceuticals and suppositories, etc. Among them, oral pharmaceuticals are formulated for rapid-acting effect. However, it is recommended to avoid taking them on an empty stomach as they have side effects such as stomach discomfort.
However, the absorption of diclofenac sodium oral pharmaceuticals is outstandingly effected on whether or not a meal has been eaten. When they are taken after eating, the initial absorption of diclofenac sodium is outstandingly reduced in the amount and delayed in the rate compared with the case where they are taken on an empty stomach, and in some cases, the maximum absorption is confirmed at several hours to ten and several hours after taking them, and also individual difference is large in the absorption thereof.
Therefore, in case where an rapid-acting effect and certainty are taken seriously, it is the present state that the pharmaceuticals are used in most cases in a form of suppository. However, there are many patients who are reluctant to use the suppositories, and therefore the suppositories can not be used as conveniently as oral pharmaceuticals. Consequently, today there is a strong request for diclofenac sodium oral pharmaceuticals having a rapid-acting effect and certainty similarly to the suppository even in case where it is taken on a non-empty stomach.
It has been already known that in order to increase an internal absorption of a pharmaceutical agent that is slightly soluble in water, the pharmaceutical agent is formulated with a surfactant to increase the solubility of the pharmaceutical agent to water.
As the prior document, Japanese Patent Laid-open No. Sho 63-277617 discloses a medicine composition for oral administration from which micelles are formed, comprising an nonsteroidal anti-inflammatory agent such as diclofenac, and a nonionic surfactant such as polyoxyethylated surfactant, sorbitan fatty acids or the like. In addition, the examples of this document describe a pharmaceutical comprising diclofenac acid and polyoxyethylated castor oil. However, this document does not describe at all the above-mentioned problem on the absorption of diclofenac sodium pharmaceutical under non-fasting condition nor means for solving the problem. Further, this document does not describe as surfactant cholic acid derivatives that are varieties of anionic surfactants.
In addition, Japanese Patent Laid-open No. Hei 8-507515 discloses a particle-suspension of colloidal solid particles in which a pharmaceutical agent being slightly soluble in water is captured with solid particles that are emulsified and stabilized by adding a lipid that is insoluble or slightly soluble in water at room temperature to nonionic surfactant and bile salts containing propylene glycol as dispersant, and this document discloses that the pharmaceutical agent includes diclofenac. However, this document has no concrete disclosure on diclofenac pharmaceuticals. Also, this document does not describe problems to be solved by the present invention nor means for solving the problems similarly to the above-mentioned Japanese Patent Laid-open No. Sho 63-277617.
As mentioned above, although it was known that diclofenac being slightly soluble in water is mixed with surfactants in order to increase solubility and dispersibility, it was not necessary to use surfactants for diclofenac sodium having a higher water-solubility, and therefore the mixing of surfactants has not been considered.